This invention relates to a novel method for converting dihydrotagetone, a bifunctional acyclic monoterpene ketone, isolated from plant species of Tagetes species into coconut flavoured 5-isobutyl-3-methyl-4,5-dihydro-2(3H)-furanone with two chiral centers of formula (1). Interestingly, the compound (1) is found as a novel analogue of whisky lactone (also named as Querecus lactone or oak lactone) of formula (1a), which is contained, for example, in high quality alcoholic beverages (Napolean whisky, Jamaica and cognac etc), as fragrance ingredient, in insect pheromones and several natural products containing this structural moiety. Moreover coconut flavoured compound (1) is also an analogue of coconut aldehyde (xcex3-nonalactone or aldehyde C-18, F.E.M.A. No. 2751) of formula (1b) which is responsible for flavouring a wide range of food stuffs including baked goods and confectionery. 
(1) No. of chiral centers=2; (1a) No. of chiral centres=2; (1b) No. of chiral center=1
The present invention also relates to 2,6-dimethyl-4-oxo-heptanoic acid of formula (3) not only as a precursor for the synthesis of whisky lactone of formula (1a) but also as a novel analogue of 2,6-dimethyl-5-oxo-heptanoic acid (a constituent of well known essential oil of Mentha x piperita) which has wide applications in flavouring food stuffs, soft and alcoholic beverages, perfumery and pharmaceutical industries.
A wide-spread class of xcex3-butyrolactones (also known as dihydro-2(3H)-furanone or 4-butanolide or tetrahydro-2-furanone) were first synthesized in 1884 via internal esterfication of 4-hydroxybutyric acid. These important lactones exhibit very intensive and pleasant fruity aroma and can be easily transformed into other useful products e.g. furans, cyclopentenones, butenolides and pyrrolidones (Freudenberger, D., Wunder, F. and Fernholz, H., U.S. Pat. No. 4,096,156 (1978)). The butyrolactone moieties are found in many natural products (Gunatilaka, A. A. L., Surendra, K. S. and Thomson, R. H., Phytochemistry, 23(4) 929-931 (1984) and Drioli, S., Felluga, F., Forzato, C., Nitti, P., Pitacco, G. and Valentin, E., J. Org. Chem., 63, 2385-2388 (1998)), insect pheromones (Naoshima, Y., Ozawa, H., Kondo, H. and Hayashi, S., Agric. Biol. Chem., 47(7) 1431-1434 (1983); Kim, C. S., Datta, P. K., Hara, T., Itoh, E. and Horiike, M., Bioscience Biotechnology and Biochemistry, 63(1) 152-154 (1999)), antifungal substances and flavor components (Shinohara, T. and Watanabe, M., J. Agri. Chem. Soc. Jap., 53 (7) 219-225 (1979) and Buttery, R. G. and Ling, L. C., J Agric Food Chem., 46(7) 2764-2769 (1998)) and also occur in the essential oil bearing plants.
Although several methods are available for the synthesis of simple xcex3-butyrolactone derivatives, however, synthesis of chiral centered biologically active xcex3-butyrolactone (Hullot, P., Cuvigny, T., Larcheveque, M. and Normant, H., Can. J. Chem., 55, 266-273 (1977); Tamaru, Y., Hojo, M. and Yoshida, Z., J. Org. Chem., 56, 1099-1105 (1991); Daugan, A. and Brown, E., J. Nat. Prod., 54(1) 110-118 (1991); Hartmann, B., Kanazama, A. M., Depres, J. P. and Greene, A. E., Tetrahedron Lett. 34(24) 3875-3876 (1993); Ishibashi, F.; Taniguchi, E., Phytochemistry, 49(2) 613-622 (1998) and Noyori, R., Kitamura, M., Ohkuma, T., Saya, N. and Kumobayashi, H., U.S. Pat. No. 5,420, 306 (1995)) and their analogues (Mangnus, E. M., Vliet, L. A. -van, Vandenput, D. A. L. and Zwanenburg, B., J. Agri. Food Chem., 40(7) 1222-1229 (1992); Belletire, J. L., Mahmoodi, N. O., J Nat. Prod., 55(2) 194-206 (1992) are tedious but even then the preparation of chiral xcex3-butyrolactones are the subject of many synthetic schemes (Carretero, J. C., Rojo, J., Tetrahedron Lett., 33, 7407-7410 (1992); Casey, M., Manage, A. C. and Murphy, P. J., Tetrahedron, 33, 965-968 (1992); Zschage, O. and Hoppe, D., Tetrahedron, 48, 5657-5666 (1992); Paulsen, H. and Hoppe, D., Tetrahedron, 48, 5667-5670 (1992); Chong, J. M. and Mar, E. K., Tetrahedron Lett., 31, 1981-1984 (1990) and Bachi, M. D. and Bosch, E. J., J. Org. Chem., 57, 4696-4705 (1992).
In particular, two chiral centered xcex3-butyrolactones having substituents such as an alkyl or alkenyl group are in more demand and they exist as either cis and/or trans isomer in nature (Bryan, V. and Chan, T. H., Tetrahedron Lett., 37(30), 5341-5342 (1996)). For example, whisky lactone, chemically known as 5-butyl-4-methyl-dihydro-2(3H)-furanone (also known as 3-methyl-4-octanolide or 4-hydroxy-3-methyloctanoic acid lactone) (1a) is a natural optically active disubstituted butyrolactone which is widely recognized and it has been identified as the most valuable additive responsible for the flavor of high quality whisky, wine, cognac and scotch etc (Nishimura, K. and Masuda, M., J. Food Sci. 36, 819 (1971); Kepner, R. E., Webb, A. D. and Muller, C. J., Am. J. Enol. Viticult, 23, 144 (1972); Etienne, M. and Manfred, S., Tetrahedron Lett., 25(40), 4491-4494 (1984) and Pxc3xa9rez-coello, M. S., Sxc3xa1nchez, M. A., Garcxc3xada, E., Gonzxc3xa1lez-vixc3x1as, M. A., Sanz, J. and Cabezudo, M. D., J. Agri. Food Chem., 48, 885-889 (2000)). Whisky lactone (1a) (also known as oak lactone or Querecus lactone) is a diastereomer of 3-methyl-4-octanolides (5-butyl-4-methyl-dihydro-2(3H)-furanone) which is found in whisky, wine, brandy and in extract of oak barrels. This lactone is important constituent of aging flavour and have so far been considered to be formed during aging from unknown precursors in wood barrels (Chem Abstr. 114, 181996v, 1991) which finally contributes to the flavour impact of the oak. The effect of oak barrels on the quality of wines are also influenced by several factors such as tree age, growth rate of tree and barrel size etc (Towey, J. P. and Waterhouse, A. L., Am. J. Enol. Viticult, 47(1), 17-20 (1996)).
In particular, the quality of the alcoholic beverages is affected largely by the presence of whisky lactone which is produced during the aging process. A wine aged for a longer period of time is realized to be of higher quality and is further influenced by several factors such as climatological conditions, fermentation, distillation, maturation and blending (Plaza, E. G., Munoz, R. G., Roca, J. M. L. and Martinez, A., J. Agric., Food Chem., 48, 736-741 (2000)). One of the isomers of this interesting whisky lactone (1a) is identified for the first time in whisky by Soumalainen and Nykanen in 1969 (Soumalainen, H. and Nykxc3xa4nen, L., Nxc3xa4brungsmiddelindustrien, 23, 1-15 (1970), however, later on cis and trans isomers have been determined by several workers in matured cognac, Jamiaca rum and whiskies and found that the aroma threshold for the cis isomer is 92 ppb while for the trans-isomer is 460 ppb (Masuda, M. and Nishimura, K., Phytochemistry, 10, 1401-1402 (1971); Gunther, C. and Mosandl, A., Liebigs Ann. Chem. 2112-2122, (1986); Gunther, C. and Mosandl, A., Z. Lebensm. Unters. Forsch., 185, 1-4 (1987) and Maarse, H. and Berg F. V. D. In Understanding Natural flavours, edited by Piggott, J. R. and Paterson, A.; Blackie Academic and Professional, New York, pp. 243-267 (1994)). In fact, four stereoisomers of whisky lactone (1b) are known with the following taste and odor such as (3R, 4R)-5-butyl-4-methyl-dihydro-2(3H)-furanone with sweet, fresh, bright coconut smell (in 10% ethanol) and creamy, soft, coconut taste (10 ppm in aqueous saccharin); (3S, 4S)-5-butyl-4-methyl-dihydro-2(3H)-furanone with weak coconut note earthy, mouldy afterodor, hay note odor and herbaceous, reminiscent of coconut taste; (3S, 4R)-furanone derivative with spicy celery note, weak coconut, distinct green walnut note odor and sweet creamy fatty, reminiscent of coconut; (3R, 4S)-furanone derivative with intensive coconut note, afterodor, reminiscent of celery odor and weak spicy, herbaceous taste (Schreier, P., In: Bioflavour ""87, Analysis. Biochemistry Biotechnology, Proceedings of the International Conference, Wxc3xcrzburg, Federal Republic of Germany, Sep. 29-30, 1987, Walter de Gruyter, New York, 55-74, (1988) and Eric, M., Raymond, B., Christine, L. G. and Jean-Louis, P., J. Agric.Food Chem., 48, 4306-4309, (2000)). A mixture of cis- and trans-whisky lactones also exhibits a repellent activity against mosquitoes and flies (Shono, Y. and Tsukasa, Y., Nippon Kokai Tokkyo Koho, 63-48203). However, considering all the above factors, it was realized that the productivity of oak lactone by aging whisky in oak barrel for several months/years in controlled temperature and other conditions is a laborious job, therefore, synthesis of whisky lactone (1a) has been developed by several chemists and some of the reported conventional methods include the following:
Typical prior art refrences include Masuda, M. and Nishimura, K., Chemistry Letters, 1333 (1981); Hoppe, D. and Bronneke, A., Tetrahedron Lett., 24, 1687 (1983)); Mori, M., Chuman, T. and Kato, K., Carbohydrate Research, 129, 73-86 (1984)); Frauenrath, H., Philipps, T., Liebigs Ann. Chem. 1951-1961 (1985)); Gxc3xcenther, C. and Mosandl, A., Liebigs Ann. Chem., 2112-2121 (1986)); Sharma, G. V. M., Vepachedu, S. R. and Chandrasekhar, S., Synth. Commun. 20, 3403 (1990); Suzuki, Y., Mori, W., Ishizone, H., Naito, K. and Honda, T., Tetrahedron Lett. 33, 4931-4932 (1992) and Takashi, E., Hajime, M., Hiroshi, K. and Koshi, K., U.S. Pat. No. 5,216,177 (1993)).
It, therefore, becomes an object of the invention to eliminate the disadvantages existing with above known methods and others and to provide a rapid and economical method for the preparation of xcex3-butyrolactone of formula (1) as an analogue of whisky lactone (nicknamed as Querecus lactone or oak lactone) of formula (1a), via oxidation of dihydrotagetone (4) into 2,6-dimethyl-4-oxo-heptanoic acid (3) followed by reduction of 3 and lactonisation into xcex3-butyrolactone (1). In addition, xcex3-butyrolactone (1) with coconut flavour can also find application in flavouring the food stuffs since its analogue i.e.coconut aldehyde (xcex3-nonalactone, F.E.M.A. No. 2751) (1b) is responsible for flavouring a wide range of food stuffs including baked goods and confectionery.
The main object of the present invention is to provide a novel compound 5-isobutyl-3-methyl-4,5-dihydro-2(3H)-furanone of formula (1) as an analogue of whisky lactone or oak lactone or querecus lactone of formula (1a)
Yet another object of the invention is to provide a process for the preparation of compound 5-isobutyl-3-methyl-4,5-dihydro-2(3H)-furanone of formula (1) starting from dihydrotagetone of formula (4) which is, in fact, a natural acyclic monoterpene ketone (dihydrotagetone) found readily in Tagetes species.
Yet another object of the invention is to provide a simple process for industrial scale purification of starting material i.e. dihydrotagetone of the formula (4) from oil of Tagetes species.
Yet another object of the invention is to provide a simple process for proper utilization of dihydrotagetone of formula (4) into high valued products.
Yet another object of the invention is to provide a simple and efficient oxidizing reagent which utilizes the double bond of dihydrotagetone to generate a novel 2,6-dimethyl-4-oxo-heptanoic acid of formula (3) with one chiral center.
Yet another object of the invention is to provide a rapid method of converting dihydrotagetone of formula (4) into 2,6-dimethyl-4-oxo-heptanoic acid of formula (3) in microwave oven ranging from 5-30 minutes.
Yet another object of the invention is to accelerate oxidation of double bond of dihydrotagetone of formula (4) into 2,6-dimethyl-4-oxo-heptanoic acid of formula (3) by using alumina as a catalyst.
Yet another object of the invention is to provide a simple process for the preparation of 2,6-dimethyl-4-oxo-heptanoic acid of formula (3) in high yield for its use as a multipurpose additive in food and tobacco products since its analogue such as 2,6-dimethyl-5-oxo-heptanoic acid (found as a constituent of an important Italo-Mitcham peppermint oil i.e. Menthaxc3x97piperita L.) is well known for its wide application in perfumery, flavour and pharmaceutical industry.
Yet another object of the invention is to convert 2,6-dimethyl-4-oxo-heptanoic acid of formula (3) into corresponding 4-hydroxy acid or 4-oxo ester or the like.
Yet another object of the invention is to provide an industrial method for the preparation of 5-isobutyl-3-methyl-4,5-dihydro-2(3H)-furanone of formula (1) in high yield and purity via reduction of above obtained 2,6-dimethyl-4-oxo-heptanoic acid of formula (3) with metal hydride followed by lactonisation into 5-isobutyl-3-methyl-4,5-dihydro-2(3H)-furanone of formula (1).
Yet another object of the present invention is to introduce two chiral centred 5-isobutyl-3-methyl-4,5-dihydro-2(3H)-furanone of formula (1) since it is well established that chiral discrimination is an important principal of odor perception.
Yet another object of the invention is to provide 5-isobutyl-3-methyl-4,5-dihydro-2(3H)-furanone of formula (1) as a new product for the first time for its wide application in flavours, perfumery, cosmetics, soft and alcoholic beverages and pharmaceutical industries for its biological activities.
Yet another object of the invention is to provide coconut flavoured 5-isobutyl-3-methyl-4,5-dihydro-2(3H)-furanone of formula (1) for its use as a substitute of several other coconut flavouring xcex3-butyrolactones for its application in food and beverage or the like.
Yet another object of the invention is to provide as an analogue of coconut aldehyde (aldehyde C-18) of formula (1b) which is one of the most frequently used lactones in perfumery and flavour industries (F.E.M.A. No. 2781).
The present invention provides a method for preparing 3,5-disubstituted xcex3-butyrolactone, via which two chiral centered lactone of formula (1) with coconut flavour, an analogue of natural whisky lactone (also named as Querecus lactone or oak lactone) of formula (1a) responsible for high quality of whisky, wine, brandy and scotch is formed by utilizing a natural inexpensive acyclic monoterpene ketone (dihydrotagetone) of formula (4), isolated from the oil of Tagetes sp., which was smoothly oxidized with meta-periodate/potassium permanganate into 2,6-dimethyl-4-oxo-heptanoic acid of formula (3). The reduction of oxo acid (3) with sodium borohydride followed by lactonisation in acidic medium furnished a new two chiral centered 5-isobutyl-3-methyl-4,5-dihydro-2(3H)-furanone of formula (1) which has wide applications in flavouring food stuffs, soft and alcoholic beverages, perfumery and pharmaceutical industries.
The present invention also relates to 2,6-dimethyl-4-oxo-heptanoic acid of formula (3) not only as a precursor for the synthesis of whisky lactone of formula (1a) but also as a novel analogue of 2,6-dimethyl-5-oxo-heptanoic acid (a constituent of well known essential oil of Menthaxc3x97piperita) which has wide applications in flavouring food stuffs, soft and alcoholic beverages, perfumery and pharmaceutical industries.